N-vinyl oxyethyl-{60 -methyl-{62 -phenethylamines

ABSTRACT

Novel N-vinyloxyethyl- Alpha -methyl- Beta -phenethylamines represented by the formula   wherein R is H, halo or CF3 and acid addition salts thereof. The compounds are useful as appetite depressants.

United States Patent (191 Horrom 5] Dec. 9, 1975 N-VINYLOXYE'I'HYL-a-ME'IHYL-fl- Primary ExaminerR. V. Hines PHENETHYLAMINESAttorney, Agent, or FirmGildo E. Fato; Robert L.

' k [75] Inventor: Bruce Wayne Horrom, Waukegan, Nlbkac Ill.

[73] Assignee: Abbott Laboratories, North {57] ABSTRACT chicagc" NovelN-vinyloxyethyl-a-methyl-B-phenethylamines 22 i Aug 16, 1974 representedby the formula [21] Appl. No; 498,013

Related US. Application Data Continuation-in-part of Ser No. 481,626,June 21, I974, abandoned References Cited UNITED STATES PATENTS 1/1956Surrey 260/5708 X wherein R is H, halo or CF and acid addition saltsthereof. The compounds are useful as appetite depressants.

6 Claims, N0 Drawings N-VINYL OXYETHYL- -METHYL-B -Pl-IENETHYLAMINESThis application is a Continuation-in-Part of US. Ser. No. 48l,626 filedJune 21, I974 and now abandoned.

BACKGROUND OF THE INVENTION Appetite suppressants commonly produce sideeffects such as acting as a stimulant. A relatively recently introducedappetite suppressant commonly known as fenfluramine and having thefollowing formula:

NHCH,CH,

CH,-CHCH,

DETAILED DESCRIPTION OF THE INVENTION This invention relates to novelphenethylamines and more particularly relates to novelN-vinyloxyethyl-amethyl-B-phenethylamines and acid addition saltsthereof which are useful as appetite depressants. The

The of this invention are represented by the formula wherein R ishydrogen, halo or trifluoromethyl and acid addition salts thereof.

The term halo" as used herein, includes chloro, fluoro, bromo and iodo.

The compounds are useful as appetite depressants when administeredorally to mammals in dosages of from 5 to 20 mg./kg. of body weightdaily.

The preparation of the compounds of this invention is represented by thefollowing reaction sequence:

cu, NaBH,

MeOH

The starting materials can be prepared by methods well known in the art.

The following examples further illustrate the present invention:

EXAMPLE 1 N-( 2-vinyloxyethyl)-a-methyl-B-phenylethylamine A solution of40.2 g. (0.3 mole) of phenylacetone, 26.2 g. (0.3 mole) of Z-aminoethylvinyl ether and 200 cc. of anhydrous benzene were heated under refluxunder a Dean-Start water separator until the theoretical amount of waterwas removed (ca. 4 hours). At the end of this time, the benzene wasremoved under vacuum and the resulting crude imine was taken up in 450cc. of dry methanol. To this solution was added 22.6 g. (0.6 mole) ofsodium borohydride in small portions over a period of 56 hour. After theaddition was complete, the reaction mixture was refluxed for 3 hours.The methanol was removed under vacuum and 300 cc. of water, I50 cc. of20% potassium hydroxide and 60 g. of potassium hydroxide were addedsuccessively and the resulting oil was extracted with ether. Afterdrying the ether solution over anhydrous magnesium sulfate, filteringand concentrating the resulting oil, it was distilled. 32.5 g. (64%yield) of the product as a colorless oil was obtained, b.p. l00-lO2/l .5mm; N 1.5070.

EXAMPLE 2 N-(2-vinyloxyethyl)-a-methyl-B-(4-chlorophenyl) ethyl aminewas prepared from 4-chlorophenylacetone and 2-aminoethylvinyl etheraccording to the method of Example 1 to yield the product (58% yield) asa colorless oil, b.p. l03l04/0.4 mm; N 1.5199.

EXAMPLE 3 Elemental Analysis Calculated Found EXAMPLE 4 N-(Z-vinyloxyethyl )-a-methyl--( 3-trifluoromethylphenyl)-ethyl amine wasprepared from 3-trii1uoromethyl-phenylacetone and 2-aminoethylvinyletheraccording to the method of Example 1. The product was obtained in 32%yield as a colorless oil, hp. 81-83/0.5 mm; N 1.4650.

EXAMPLE 5 N-( 2-vinyloxyethyl)-a-methyl-B-( 3-trifluoromethylphenyl)Phenethylamine Hydrochloride A solution of 12.4 g. (0.0454 mole) aminein 50 ml. anhydrous ether was treated with 25 ml. of 1.2N ethanol-HCl atice bath temperature. After cooling overnight at the product wascollected by filtration and washed with anhydrous ether. Obtained 1 1.2g. (80%), MP 117-1 18.5. The salt is soluble in water.

Elemental Analysis Calculated Found C 54.29 54. l 7 H 6.1 8 6.27 N 4.524.54

EXAMPLES 6-8 4 erally include a pharmaceutically acceptable carrier ordiluent such as lactose, starch or sucrose along with lubricating agentssuch as magnesium stearate and flavon ing and sweetening agents and thelike.

The components of the present invention, particularly the hydrochloridesalts of the compounds of formula B in which R is Cl or CF;, haveminimum stimulating properties and are considerably less toxic thanfenfluraminee and considerably more potent as illustrated by thefollowing data.

Acute Toxicity in Rats As illustrated in Table I, the hydrochloridesalts of the compounds of formula B in which R is C1 or CF areapproximately four times less toxic than fenfluramine.

Table I Reduction of Food Comsumption in Rats Dose, gm/kg, MortalityCompound Post as (P.O.) Ratio Fenfluramine 0.1 0/6 0.2 2/6 0.25 416 0.35/6 Calculated LD 0.225 gm/kg (0.19-0.26)

HCl Salt,

R=Cl 0.25 0/6 0.5 U6 1.0 3/6 1.25 4/6 1.50 5/6 2.00 6/6 Calculated LD0.95 gm/kg (0.658-1 .333)

HCl Salt,

R=CF 0.5 016 0.75 l/6 0.85 216 1.0 4/6 2.0 516 Calculated LD 1.01 gm/kg(0765-1333) Table 11 records the percent change in average dailyconsumption of food at various dosage levels upon administration offenfluramine or the HCl salt of the compounds of formula B in which R isC1 or CF;, as well as the dose in milligrams per killograms necessary toreduce the intake offood by 50% (ED 50). The data illustrates that thecompound in which R is Cl is approximately 2.5 times more potent thanfenfluramine while the compound in which R is CF is almost 1.2 times aspotent. in this study, drugs were administered one hour prior to feedingon the fifth day of regular food intake at doses of 5, 10 and 20milligrams per killogram, with five rats being dosed at each level andfifteen rats serving as controls.

Table ll-continued Change From Control 'ED dose (mg/kg) necessary toreduce the intake of food by 50%.

The effect of pre-treatment with fenfluramine and the HCI salts of thecompounds of formula B in which R is Cl or CF, on rat serum lipids andglucose induced by olive oil gavage was studied and found to inhibit thesharp rise of triglycerides.

[t has been reported that treatment of rats with fenfluramine evoked arapid increase in the concentration of plasma free fatty acids (Bizzi,A. et al. Amphetamines and Related Compounds, Raven Press, New York(1970)). Despite the increased fatty acid levels, the drug also produceda decrease in plasma triglycerides in fed, but not fasted, animals(Garattini, S. et al. Advan. Exp. Med. Biol, 26, 103 (l972)). Thetriglyceride-lowering effect of fenfluramine has been correlated atleast partially, to inhibition of the intestinal absorption oftriglycerides (Bizzi, A. et al. J. Pharmacol., 23, 131 (1973)). It hasbeen demonstrated that the Results A summary of the serum parametersmeasured after the 5 hour experimental period is given in Table III. Thedata show the following:

i. All of the animals receiving olive oil alone or olive oil and drugshowed a 2.5-3.3 fold increase in serum free fatty acids when comparedto untreated control 7 rats. The elevation in free fatty acids isprobably related to both the oil and the drugs.

2. The HCI salts of the compounds of formula B wherein R is Cl or CF,were comparable to fenfluramine in inhibiting the increase in serumtriglycerides induced by olive oil gavage 50-55% of the oil treatedgroup).

3. The rise in serum glycerol levels induced by olive oil was onlyslightly inhibited by prior treatment with the drugs (16-35%).

4. Serum glucose concentrations remained relatively unchanged in controland treated groups.

5. Under these conditions, olive oil apparently induced a 45% increasein serum cholesterol. This increase was unaffected by fenfluraminepretreatment, but was reduced l4-l9% by the HCI salts of the compoundsof formula B in which R is Cl or Cl}.

Table III Serum Free Olive Fatty Acids Serum Concentration (mg%)Pre-trcatment Oil pEq/liter Triglycerides Glycerol Cholesterol GlucoseNone 3021' I3 46: 3 [31.20 97: 6 146110 None 736$ 55 135136 2.5:.20 l4]:4 l56i 7 Fenfluramine 9l9i 6] 611 l l.6i.l0 i401 3 [60 9 R=Cl, HCl Salt780: 66 621* 7 l.8i.30 H6: 8 l59i l R=CF;,, HCl Salt 870: 6l 621-[3211.40 122:10 I59: 7

Methods Twenty-four male Sprague Dawley rats (200-250 g.) were dividedinto 8 groups as follows:

Pretreatment Dose Olive Number of Drug (mg/kg) Oil Rats None 3 None 3Fenfluramine 20 3 R=Cl, HCl Salt 20 3 R=CF;|. HCI Salt 20 3 '20 ml/kg bygavagc The animals were not fasted. Where indicated, the rats werepre-treated (intraperitoneally) with the appropriate drug for 2 hoursprior to the administration of olive oil. Three hours after olive oiltreatment, the animals were anesthetized with ether and blood samplesobtained by cardiac puncture of the exposed heart. in each case. totaltreatment time was 5 hours.

Sidman Avoidance Test in the Rat The compound fenfluramine and the HClsalt compound of formula B in which R is Cl were examined in the SidmanAvoidance test. The date for the fenfluramine studies show all doses tobe effective in producing significant results. The administration offenfluramine produced results indicative of amphetamine-like compounds,the same increase in response rate and accompanying decrease in shockrate. The HCI salt of the compound of formula B in which R is Cl did notaffect performance significantly overall, producing only a sharpdecrease in shock rate with response rate remaining stable.

Fenfluramine was run as a standard compound for comparative purposes inthe study of appetite-suppressing drugs. The effects of drug-inducedbehavior are evaluated using the technique of Sidman Avoidance (Sidman,M., J. Comp. Physiol. Psychol.

Male, Long Evans black-hooded rats (Simonsen Labs) weighingapproximately 500 grams are run individually in Lehigh ValleyElectronics rodent test cham- 60 bers. Sessions (day/night) are 7.5hours and 14 hours in length, respectively. The paradigm consists of twodistinct temporal intervals for neither of which is the rat given anyexteroceptive cues. The amount of time that elapses between shocksdesignates the shock-shock interval, is ofa predetermined fixed length(10 seconds),

and programmed by a recycling timer. When the rat responds by pressing alever, the shock-shock interval is terminated and the response-shockinterval is started.

This interval is also of a predetermined fixed length (30 seconds) andprogrammed by a recycling timer. Both timers never operatesimultaneously. The responseshock interval begins anew each time the ratresponds on the lever. If the interval should elapse without the ratresponding, a shock (0.5 seconds, mA) is given via the grid floor andthe response-shock interval ends and the shock-shock interval begins.

Drug effects are evaluated as a percentage deviation of the ratsbehavior from his baseline rate (responses/- minute and shocks/minute).These effects are analyzed in minute segments and an overall percentagedeviation (response index and shock index) is determined.

Table IV The results shown in the following table are based on an 8mg/kg oral dose.

Number of rats: 4 Session length: 7.5 hours Compound Response Rate ShockRate Fenfluramine +l5 50 R=Cl, HCl Salt 7 S5 5 mg/kg),

Symtomatology Tests in the Mouse In contrast to fenfluramine andmethamphetamine which show stimulant effects at low doses (l050 only aweak stimulatory effect was observed at high doses (300-1000 mg/kg) forthe HCl salt of the compound of formula B in which R is C].

What is claimed is:

1. A compound of the formula R cu,

wherein R is hydrogen, halo or trifluoromethyl, and acid addition saltsthereof.

2. A compound in accordance with claim I, N-(Z-vinyloxyethyl)-a-methyl-B-phenethylaminc.

3. A compound in accordance with claim 1, N-(2-vinyloxyethyl)-a-methyl-fl-(4-chlorophenyl)ethyla- 4. The hydrochloridesalt of the compound of claim 3.

5. A compound in accordance with claim 1, N-(Z-vinyloxyethyl)-x-methyl-B-(3-trifluoromethylphenyl)- phenethylamine.

6. The hydrochloride salt of the compound of claim 5.

1. A COMPOUND OF THE FORMULA
 2. A compound in accordance with claim 1,N-(2-vinyloxyethyl)-Alpha -methyl- Beta -phenethylamine.
 3. A compoundin accordance with claim 1, N-(2-vinyloxyethyl)-Alpha -methyl- Beta-(4-chlorophenyl)ethylamine.
 4. The hydrochloride salt of the compoundof claim
 3. 5. A compound in accordance with claim 1,N-(2-vinyloxyethyl)-Alpha -methyl- Beta-(3-trifluoromethylphenyl)phenethylamine.
 6. The hydrochloride salt ofthe compound of claim 5.